Chronic kidney disease (CKD) affects approximately 26 million people in the United States. End stage renal disease (ESRD), the final stage of CKD, requires renal replacement therapy such as hemodialysis (HD). Patients undergoing HD are at increased risk of developing cardiovascular complications, and this risk is not explained by traditional cardiovascular risk factors. Other factors such as inflammation and oxidative stress may contribute to the pathophysiology of cardiovascular events in patients with ESRD. We have previously shown that bradykinin plays a role in inflammation in patients on HD and increases oxidative stress in vitro. Mitochondria are one of the main sources of oxidative stress;however the role of mitochondrial dysfunction in ESRD is not yet understood. The overarching goal of this study is to determine the role of progressive CKD and the activation of the kalikrein-kinin system during HD on the development of mitochondrial dysfunction;we will measure mitochondrial function using the gold standard method, 31P magnetic resonance spectroscopy.
In Specific Aim 1 we will test the hypothesis that mitochondrial function worsen with the progression of kidney disease. We will compare patients undergoing chronic HD, patients with CKD not yet on HD, and control subjects without CKD. Participants will be matched by age, sex, diabetic status, and BMI.
In Specific Aim 2 we will test the hypothesis that endogenous bradykinin promotes mitochondrial dysfunction in patients undergoing HD. We will first perform a randomized, placebo-controlled, double-blind, cross-over study measuring the effect of HOE-140 (Icatibant), a bradykinin B2 receptor blocker, on mitochondrial function. We will also evaluate patients undergoing HD that have been treated for 3 months with the ACE inhibitor ramipril versus the ARB valsartan or placebo, as part of an ongoing NIH funded clinical trial (NCT00878969). We anticipate that bradykinin B2 receptor blockade with HOE-140 will improve mitochondrial function during HD;whereas ramipril, which increases endogenous bradykinin, will worsen mitochondrial function. The candidate obtained his Ph.D. in Physiology in the University of Kentucky and completed postdoctoral training in Clinical Pharmacology at Vanderbilt University. The candidate has studied mitochondrial biology and muscle physiology in rodents, and has conducted a clinical trial in patients with CKD. This award will allow the candidate to strengthen his expertise in studying mitochondrial function in humans and to acquire the skills necessary for an independent career as a physician-scientist. Dr. Nancy J. Brown (candidate's mentor) is an NIH-funded investigator with a successful record of mentoring physicians to scientific independence. As Associate Dean for Clinical Translational Scientist Development (2006 to 2010), Dr. Brown developed the infrastructure and environment to promote the success of junior physician-scientists. The institution is committed to the success of the candidate's career development plan and the completion of the research plan.

Public Health Relevance

No pharmacological intervention has effectively reduced cardiovascular morbidity and mortality in patients with end stage renal disease (ESRD). This study will assess the role of progressive kidney disease and the activation of the kalikrein-kinin system during hemodialysis on mitochondrial function. Understanding the mechanism leading to mitochondrial dysfunction will help us to develop new therapeutic approaches to reduce the cardiovascular complications in patients with ESRD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23DK100533-01
Application #
8617984
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2013-09-10
Project End
2018-06-30
Budget Start
2013-09-10
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$152,230
Indirect Cost
$11,106
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Udpa, Nitin; Ronen, Roy; Zhou, Dan et al. (2014) Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol 15:R36